Description
Parkinson's disease (PD), the second most common age-related progressive neurodegenerative disorder, is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. Zonisamide is an-anti-convulsant drug that has recently been shown to improve clinical symptoms of PD through its inhibition of monoamine oxidase B (MAO-B). However, zonisamide has additional targets, including voltage-gated sodium channels (Nav), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Nav1.6 is highly expressed in microglia of post-mortem PD brain and of mice treated with the parkinsonism-inducing neurotoxin MPTP. Administration of zonisamide (20mg/kg, i.p. every 4hx3) following a single injection of MPTP (12.5mg/kg, s.c.) reduced microglial Nav 1.6 and microglial activation in the striatum, as indicated by Iba-1 staining and mRNA expression of F4/80. MPTP increased the levels of the pro-inflammatory cytokine TNF-alpha and gp91(phox), and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down-regulation of microglial Nav 1.6. Thus, in addition to its effects on parkinsonian symptoms through inhibition of MAO-B, zonisamide may have disease modifying potential through the inhibition of Nav 1.6 and neuroinflammation.
Subject
Female; Humans; Male; Animals; Mice; Aged; *gp91(phox); *Microglia; *MPTP; *Na(v)1.6; *Neuroinflammation; *Parkinson's disease; *TNF-alpha; *Voltage-gated sodium channels; *Zonisamide; Inflammation/metabolism; Neuroprotective Agents/pharmacology; Antiparkinson Agents/*pharmacology; Inbred C57BL; Microglia/drug effects/*metabolism; NAV1.6 Voltage-Gated Sodium Channel/*biosynthesis; Parkinsonian Disorders/*metabolism/pathology; Zonisamide/*pharmacology